Martin Krause Neurophysiology - Copy - Copy

7/28/2019 Martin Krause Neurophysiology - Copy - Copy

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Page 2 of 63Neurophysiology of treatment with traction


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3/5/2013http://www.back-in-business-physiotherapy.com/physiotherapy-teaching/neurophysiology-o...


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See Cochrane report (2006)




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amazingly, a decade after the realisation that immediate normalisation of neurological signs and

symptoms can occur if the appropriate dose of traction is applied, the research evidence still doesn'tjustify it's use.




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Note that the sinuvertebral nerve is a peripheral nerve




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Through the normalisation of muscle spasm, the amount of'force closure' around the spine shouldreduce. Consequently, such a reduction in muscle tension should reduce compressive forces on the




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intervertebral discs and blood vesels of the intervertebral foramen as well as the spinal canal

(Batson's venous plexus).

Normalisation of pressure around the dorsal root ganglion (DRG) should reduce the propagation ofectopic impulses to the spinal cord and moreover improve the afferent-efferent interaction in the

periphery. The latter would improve the modulation of blood flow as well as the modulation ofneurogenic inflammation. It should be remembered that the sinuvertebral nerve is a peripheral nerve

responsible for these effects within the intervertebral foramen and spinal canal.

Sympathetic-sensory coupling after L5 spinal nerve lesion in the rat and its relation to

changes in dorsal root ganglion blood flow

H. -J. Haebler, S. Eschenfelder, X. -G. Liu and W. JaenigPhysiologisches Institut, Christian-Albrechts-Universitt, Olshausenstrasse

40, 24098 Kiel, GermanyReceived 6 December 1999; revised 2 March 2000; accepted 17 March2000. Available online 9 October 2000.

Abstract

Transection of the L5 spinal nerve in rats results in allodynia- andhyperalgesia-like behavior to mechanical stimulation which are thought to

be mediated by ectopic activity arising in lesioned afferent neurons mainlyin the dorsal root ganglion (DRG). It has been suggested that theneuropathic pain behavior is dependent on the sympathetic nervous




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system. In rats 356 days after L5 spinal nerve lesion, we tested responses

of axotomized afferent fibers recorded in the dorsal root of the lesionedsegment to norepinephrine (NE, 0.5 g/kg) injected intravenously and toselective electrical stimulation of the lumbar sympathetic trunk (LST). In

some experiments we measured blood flow in the DRG by laser Dopplerflowmetry. The majority of lesioned afferent fibers with spontaneous

activity responded to neither LST stimulation (82.4%) nor NE (71.4%). Inthose which did react to LST stimulation, responses occurred only at highstimulation frequencies (likely to be above the physiological range), and

they could be mimicked by non-adrenergic vasoconstrictor drugs(angiotensin II, vasopressin). Excitatory responses to LST stimulation were

closely correlated with the stimulation-induced phasic vasoconstrictions inthe DRG. We therefore hypothesized that the activation of lesionedafferents might be brought about indirectly by an impaired blood supply to

the DRG. To test this hypothesis we induced a strong and sustainedbaseline vasoconstriction in the DRG by blocking endothelial nitric oxide

synthesis with N G -nitro- -arginine methyl ester ( -NAME) appliedsystemically. -NAME enhanced baseline vascular resistance in the DRG

about threefold and also increased stimulation-induced vasoconstrictions.After -NAME, the majority of axotomized neurons with spontaneousactivity were activated by LST stimulation (76%) or NE (75%). Again,

activations closely followed stimulation-induced phasic vasoconstrictionsin the DRG provided that a critical level of vasoconstriction was exceeded.In the present study, inhibitory responses to LST stimulation were

generally rare and could be reversed to activation by prolonged stimulationor after -NAME. These results show that sympathetic-sensory couplingoccurs only in a minority of axotomized afferents after L5 spinal nerve

injury. Like previous studies, they cast doubt on the notion that the L5spinal nerve lesion is a good model for sympathetically maintained pain.

Since responses of lesioned afferent neurons to LST stimulation and NEcould be provoked with high reliability after inducing vasoconstriction inthe DRG, and since they mirrored stimulation-induced vasoconstrictions in

the DRG, it appears that in this model the association of sympatheticactivity with afferent discharge occurs mainly when perfusion of the DRG

is impaired.

Author Keywords: Neuropathic pain; L5 spinal nerve injury;Sympathetically maintained pain; Dorsal root ganglion; Neurogenic

vasoconstriction; Sympathetic nervous system

Link to Pain Journal

If one considers the sinuvertebral nerve to be a peripheral nerve then inudction of

inflammation around the DRG can in turn create changes within the DRG which leads to

hyperalgesia. Clearly a viscious cycle may ensue.




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Induction of high mobility group box-1 in dorsal rootganglion contributes to pain hypersensitivity after

peripheral nerve injury

Pain, Volume 149, Issue 3, Pages 514-521 (June 2010)

Masayuki Shibasaki1, Mika Sasaki1, Mayumi Miura1, Keiko Mizukoshi1,Hiroshi Ueno, Satoru Hashimoto, Yoshifumi Tanaka, Fumimasa

AmayaCorresponding Author Information1email address

Received 3 June 2009; received in revised form 21 January 2010; accepted

17 March 2010. published online 14 April 2010.

Abstract

Pro-inflammatory cytokine high mobility group box-1 (HMGB-1) isinvolved in inflammation in the central nervous system, but less is known

about its biological effects in the peripheral nervous system. In the presentstudy, the role of HMGB-1 in the primary afferent nerve was investigatedin the context of the pathophysiology of peripheral nerve injury-induced

pain hypersensitivity. Real-time PCR confirmed an increase in HMGB-1mRNA expression in the dorsal root ganglion (DRG) and spinal nerve at

1day after spinal nerve ligation (SNL). Induction of HMGB-1 mRNA wasobserved in both injured L5 and uninjured L4. Immunohistochemistry forHMGB-1 revealed that SNL-induced HMGB-1 expression in the primary

afferent neurons and satellite glial cells (SGCs) in the DRG, and inSchwann cells in the spinal nerve. Up-regulation of HMGB-1 was

associated with translocation of its signal from the nucleus to the

cytoplasm. Injection of HMGB-1 into the sciatic nerve produces transientbehavioural hyperalgesia. Neutralizing antibody against HMGB-1

successfully alleviated the mechanical allodynia observed after SNLtreatment. Receptor for advanced glycation end products (RAGE), one of

the major receptors for HMGB-1, was expressed in the primary afferentneurons and SGCs in the DRG, as well as in Schwann cells in the spinalnerve. These results indicate that HMGB-1 is synthesized and secreted into

the DRG and spinal nerve, and contributes to the development ofneuropathic pain after nerve injury. Blocking HMGB-1/RAGE signalling

might thus be a promising therapeutic strategy for the management ofneuropathic pain.




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Conditioned stimulus and unconditioned stimulus inputs converge on individual cells in

the lateral amygdala, which is the principal output nucleus of fear system projects toareas of the hypothalamus and brainstem that control behavioural, endocrine, and

autonomic conditional responses associated with fear learning (Goldstein JA 2004). Inneurosomatic disorders, an accentuation of the attentional weighting is given toelements of a stimulus that, in actuality, have a very tenuous relationship to the state of

activation of the long-term memory store. Unlike the individual with a normallyfunctioning neural network for associated learning, the activated memory store to

which the stimulus is associated does not rapidly decay but continues to be highlyweighted, even if this weighting is outside the individual's attention (Newport DJ,Nemeroff CV 2000; in Goldstein JA 2004).

Attentional resources are allocated in favour of unexpected salient events. The term'switching' is used to denote reallocation processes, and 'salient' is used to refer tostimuli with special biological significance. Dopaminergic output is involved in

'behavioural orienting', the allocation of attention to a particular stimulus. Thisresponse normally extinguishes rapidly. Unexpected rewards or punishments lead to

the acquisition of new conditioned responses. Dopaminergic activity is suppressedwhen expected rewards fail to materialize. Basal ganglia have evolved to resolveconflicts of multiple subsystems competing for access to limited motor or cognitive

resources ( see orienteering section of website for more details ). The frontal eye fields

brings visual stimuli into the most active perceptual area of the retina, so it's potentialreward significance can be determined. The computations of the possible reward occurbefore the behavioural switch occurs, and a signal is often lost before the identity of thestimulus is fully known (Goldstein JA 2004).

The prefrontal cortex (PFC) and noradrenergic systems are both important forattentional regulation. Lesions of the PFC impair the ability to sustain attention to

relevant information and to inhibit processing of irrelevant stimuli. Neurones in thelocus coereleus (LC) fire in relation to the attentional state, and the PFC is one of the




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few high-order inputs to the LC and is an important regulator of it's activity.

Noradrenaline is known to enhance signal-to-noise ratio in sensory cortices. Withinsufficient noradrenergic stimulation, small signals may be obscured (targets) whilepotent stimuli may be processed (distractors). If noradrenaline is hypersecreted, it

would take the PFC 'off line'. The PFC may be responsible for exploratory responses ina fear-inducing environment (Goldstein JA 2004). Therefore, higher centres are most

probably involved in assessing the visual input during the assessment of signs andsymptoms.

Placebo versus Nocebo effect

Mechanisms of placebo analgesia: rACC recruitment of a subcortical antinociceptive network

U. Bingela, b,

, J. Lorenzc, E. Schoell

a, C. Weiller

dand C. Bchel

a NeuroImage Nord, Institute for Systems Neuroscience, University Medical CenterHamburg Eppendorf, Germany

b NeuroImage Nord, Department of Neurology, University Medical Center HamburgEppendorf, Germanyc Department of Physiology, University Medical Center Hamburg Eppendorf, Germany

d Department of Neurology, University of Freiburg, Germany

Received 31 January 2005; revised 19 July 2005; accepted 18 August 2005. AIB-05768. Available online 20 December 2005

Abstract

Placebo analgesia is one of the most striking examples of the cognitive modulation of

pain perception and the underlying mechanisms are finally beginning to be understood.




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According to pharmacological studies, the endogenous opioid system is essential for

placebo analgesia. Recent functional imaging data provides evidence that the rostralanterior cingulate cortex (rACC) represents a crucial cortical area for this type ofendogenous pain control. We therefore hypothesized that placebo analgesia recruits

other brain areas outside the rACC and that interactions of the rACC with these brainareas mediate opioid-dependent endogenous antinociception as part of a topdown

mechanism. Nineteen healthy subjects received and rated painful laser stimuli to thedorsum of both hands, one of them treated with a fake analgesic cream (placebo).Painful stimulation was preceded by an auditory cue, indicating the side of the next

laser stimulation. BOLD-responses to the painful laser-stimulation during the placeboand no-placebo condition were assessed using event-related fMRI. After having

confirmed placebo related activity in the rACC, a connectivity analysis identifiedplacebo dependent contributions of rACC activity with bilateral amygdalae and theperiaqueductal gray (PAG). This finding supports the view that placebo analgesia

depends on the enhanced functional connectivity of the rACC with subcortical brainstructures that are crucial for conditioned learning and descending inhibition of

nociception.

Keywords: Pain; Placebo; rACC; fMRI; PAG; Amygdala; PPI

Corresponding author. Address: NeuroImage Nord, Bldg. S 10, University Medical

Center Hamburg Eppendorf, Martinistr. 52, D-20246 Hamburg , Germany . Tel.: +4940 42803 9962; fax: +49 40 42803 9955.

Link to Pain Journal : Volume 120, Issues 1-2 , January 2006, Pages 8-15

Dissection of perceptual, motor and autonomic components of brain activityevoked by noxious stimulation


M. Pichacef, M. Arsenaultcde, P. Rainville

Received 15 April 2009; received in revised form 29 December 2009; accepted 11

January 2010. published online 23 April 2010.Abstract

In the past two decades, functional brain imaging has considerably advanced ourknowledge of cerebral pain processing. However, many important links are stillmissing in our understanding of brain activity in relation to the regulation of pain-

related physiological responses. This fMRI study investigates the cerebral correlates of

pain (rating), motor responses (RIII-reflex) and autonomic activity (skin conductanceresponse; SCR) evoked by noxious electrical stimulation. Stimulus intensity wasadjusted individually based on the RIII threshold to control for differences in peripheralprocesses and baseline spinal activation. Covariance analyses were used to reveal

individual differences in brain activity uniquely associated with individual differencesin pain, RIII and SCR. Shock-evoked activity in cingulate, medial orbitofrontal and

parahippocampal regions predicted pain sensitivity. Moreover, lateral orbitofrontal andcingulate areas showed strong positive associations with individual differences inmotor reactivity but negative associations with autonomic reactivity. Notably,




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individual differences in OFC activation was almost fully accounted by the

combination of individual measures of autonomic and motor reactivity (R2=0.93).Additionally, trial-to-trial fluctuations of RIII-reflex and SCR (within-subjects) wereproportional to shock-evoked responses in subgenual cingulate cortex (RIII), anterior

insula (SCR) and midcingulate cortex (SCR and RIII). Together, these results confirmthat individual differences in perceptual, motor, and autonomic components of pain

reflect robust individual differences in brain activity. Furthermore, the brain correlatesof trial-to-trial fluctuations in pain responses provide additional evidence for a partialsegregation of sub-systems involved more specifically in the ongoing monitoring, and

possibly the regulation, of pain-related motor and autonomic responses.

Abbreviations: ACC, anterior cingulate cortex, aINS, anterior insula, AMY, amygdala,

BA, Brodmann area, BOLD, blood oxygen level dependant, dlPFC, dorsolateralprefrontal cortex, dPCC, dorsal posterior cingulate cortex, EMG, electromyographicrecording, IFG, inferior frontal gyrus, INS, insula, IPL, inferior parietal lobule, MCC,

midcingulate cortex, mPFC, medial prefrontal cortex, OFC, orbitofrontal cortex, PAG,periacqueductal gray matter, PCC, posterior cingulate cortex, PCG, precentral gyrus,

PCL, paracentral lobule, PFC, prefrontal cortex, pgACC, perigenual anterior

cingulate cortex, PHG, parahippocampal gyrus, PMC, premotor cortex, PVA, parietalventral area, sACC, subgenual anterior cingulate cortex, SCR, skin conductance

response, SI, primary somatosensory cortex, SII, second somatosensory cortex, SMA,supplementary motor cortex, VAS, visual analogue scale

The Neuromatrix

According to Melzack (1999) the sensory-discriminative, affective-motivational and

evaluative-cognitive dimensions of pain experience are determined by the multipleinputs that act on the neuromatrix programmes. These include sensory inputs, visual

inputs which influence the cognitive interpretation of the situation, phasic and toniccognitive inputs from other areas of the brain, intrinsic neural inhibitory modulation,activity of the body's stress-regulation systems including cytokines, as well as

endocrine, autonomic, immune and opioid systems. Therefore, the role of mechanicaltraction within a multi-modal approach would be a useful clinical research paradigm.




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Multimodal approach to treatment of musculoskeletal conditions.

Chronic stress may have a direct influence on pain.

Increased basal mechanical pain sensitivity but decreased perceptual wind-up in a human model of

relative hypocortisolism




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Linn K. Kuehla, Gilles P. MichauxbCorresponding Author Informationemail address,Steffen Richtera, Hartmut Schchingera, Fernand Antonb

Received 5 October 2009; received in revised form 18 March 2010; accepted 19 March

2010. published online 09 April 2010.

Abstract

Clinical data have accumulated showing that relative hypocortisolism, which may be

regarded as a neuroendocrinological correlate of chronic stress, may be a characteristicof some functional pain syndromes. However, it has not been clarified yet whetherderegulations of the hypothalamuspituitaryadrenal (HPA) axis may directly alter pain

perception and thus be causally involved in the pathophysiology of these disorders. Totest this hypothesis, we performed a randomized placebo-controlled crossover trial in

N=20 healthy drug-free volunteers (median age 24yrs) and analyzed the effects ofmetyrapone-induced hypocortisolism on quantitatively assessed basal mechanical pain

sensitivity (1.513m/s impact stimuli), perceptual wind-up (9m/s impact stimuli at1Hz) and temporal summation of pain elicited by inter-digital web pinching (IWP; 10Npressure stimuli for 2min). Experimentally induced hypocortisolism significantlydecreased pain detection thresholds and augmented temporal summation of IWP-

induced pain (p


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The 2 threshold hypothesis of dose suggests that a therpeutic dose (normalisation of signs and

symptoms) for lumbar spine traction occurs at a very low threshold of around 12-14kg and anotherthreshold occurs with a deterioration of signs and symptoms at around 20-25kg. These values vary

to some extent depending on the stage, stability, irritability and stability of the disorder.




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Therefore, it appears to be important to engage the client in the clinical reasoning

process. In so doing, they are not passive recipients of treatment. Rather, theircognitive processes are involved with the aims and objectives of treatment as well as

expected outcome. Additionally, their motor systems are involved not only in the re-evaluation of signs, but also in the re-establish of correct muscle co-ordination andstability post traction. Importantly, general consensus suggests that multi-modal

treatment approaches within the clinical reasoning frame of reference is moreefficacious than using one modality alone. Hence, treatment with mechanical traction

should be integrated with other techniques such as joint mobilisations of the hip &thoracic spine, muscle energy techniques, soft tissue massage, trigger point massage,fascial release, dry needling, taping, and exercise regimes appropriate for the stage,

stability, severity, & irritability of the disorder, whilst respecting biomechanicalprinciples of inverse dynamics.

It should be noted however, that patients who have high scores on the Catastrophizing

Scale of the CSQ (Coping Stratagies Questionnaire : Rosentiel & Keefe 1983), whoendorse passive coping strategies on the PMI (Pain Management Inventory : Brown et

al 1989), who demonstrate low self efficacy regarding their ability to manage their painon the PSEQ (Pain self efficacy questionnaire : Lorig et al 1989), who describethemselves as disabled by their pain on the SOPA (Survey of pain attitudes : Jensen et

al 1987), and who report negative thoughts about their pain on the INTRP (Inventory of

negative thoughts in response to pain : Gil et al 1990) are at greatest risk for poortreatment outcome (Jamison 2004).

For more information on Musculoskeletal Low Back Pain and treatments LBPTreatment Progress.

Further evidence regarding psychological aspects of pain and impaired brainprocessing come from the following recent investigations :




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Chronic pain patients are impaired on an emotional decision-making task

A. Vania Apkariana, Yamaya Sosa a, Beth R. Krauss b, P. Sebastian Thomas c, Bruce E.

Fredrickson d, Robert E. Levy e, R. Norman Harden fand Dante R. Chialvo a

a Department of Physiology, Northwestern University Medical School, 303 E ChicagoAvenue, Chicago, IL 60611, USA

b Department of Neurosurgery, Upstate Medical University SUNY Syracuse, Syracuse,NY 13210, USAc Department of Anesthesia, Upstate Medical University SUNY Syracuse, Syracuse,

NY 13210, USAd Department of Orthopedics, Upstate Medical University SUNY Syracuse, Syracuse,

NY 13210, USAe Neurosurgery Department, Northwestern University Medical School, Chicago, IL60611, USA

f Rehabilitation Institute, Northwestern University Medical School, Chicago, IL 60611,USA

Received 26 June 2003; Revised 4 November 2003; accepted 15 December 2003 AIB-16048 Available online 20 April 2004.

Abstract

Chronic pain can result in anxiety, depression and reduced quality of life. However, itseffects on cognitive abilities have remained unclear although many studies attempted to

psychologically profile chronic pain. We hypothesized that performance on anemotional decision-making task may be impaired in chronic pain since human brainimaging studies show that brain regions critical for this ability are also involved in

chronic pain. Chronic back pain (CBP) patients, chronic complex regional pain

syndrome (CRPS) patients, and normal volunteers (matched for age, sex, andeducation) were studied on the Iowa Gambling Task, a card game developed to studyemotional decision-making. Outcomes on the gambling task were contrasted toperformance on other cognitive tasks. The net number of choices made from

advantageous decks after subtracting choices made from disadvantageous decks onaverage was 22.6 in normal subjects ( n =26), 13.4 in CBP patients ( n =26), and -9.5 inCRPS patients ( n =12), indicating poor performance in the patient groups as compared

to the normal controls (P


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Michael J.L. Sullivan a, Mary E. Lynch and A.J. Clark , c

a Department of Psychology, University of Montreal, C.P. 6128 Succ Centre Ville,Montreal, Que., Canada H3C 3J7

b Pain Management Unit, Queen Elizabeth II Health Sciences Centre, DalhousieUniversity, Halifax, NS, Canadac Department Anesthesia, Pain Management Unit, Queen Elizabeth II Health Sciences

Centre, Dalhousie University, Halifax, NS, Canada

Received 3 July 2004; revised 13 October 2004; accepted 1 November 2004.Available online 9 December 2004.

Abstract

The objective of the present study was to examine the relative contributions of differentdimensions of catastrophic thinking (i.e. rumination, magnification, helplessness) to thepain experience and disability associated with neuropathic pain. Eighty patients with

diabetic neuropathy, post-herpetic neuralgia, post-surgical or post-traumatic

neuropathic pain who had volunteered for participation in a clinical trial formed thebasis of the present analyses. Spontaneous pain was assessed with the sensory andaffective subscales of the McGill Pain Questionnaire. Pinprick hyperalgesia anddynamic tactile allodynia were used as measures of evoked pain. Consistent with

previous research, individuals who scored higher on a measure of catastrophic thinking(Pain Catastrophizing Scale; PCS) also rated their pain as more intense, and rated

themselves to be more disabled due to their pain. Follow up analyses revealed that thePCS was significantly correlated with the affective subscale of the MPQ but not withthe sensory subscale. The helplessness subscale of the PCS was the only dimension of

catastrophizing to contribute significant unique variance to the prediction of pain. ThePCS was not significantly correlated with measures of evoked pain. Catastrophizing

predicted pain-related disability over and above the variance accounted for by painseverity. The findings are discussed in terms of mechanisms linking catastrophicthinking to pain experience. Treatment implications are addressed.

Keywords: Catastrophizing; Helplessness; Neuropathic pain; Affective pain

Pain (2005) 113, 310-315

Self-management of chronic pain: a population-based study

Fiona M. Blyth a, Lyn M. Marchb, Michael K. Nicholas a and Michael J. Cousins b

a Pain Management and Research Institute, University of Sydney, Royal North ShoreHospital, St Leonards, NSW 2065, Australia

b Department of Rheumatology, University of Sydney, Royal North Shore Hospital, StLeonards, NSW 2065, Australia

Received 3 May 2004; revised 6 September 2004; accepted 22 October 2004. AIB-400572. Available online 25 December 2004.




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Abstract

While effective self-management of chronic pain is important, clinic-based studiesexclude the more typical pattern of self-management that occurs in the community,often without reference to health professionals. We examined specific hypotheses about

the use of self-management strategies in a population-based study of chronic painsubjects. Data came from an Australian population-based random digit dialling

computer-assisted telephone survey and included 474 adults aged 18 or over withchronic pain (response rate 73.4%). Passive strategies were more often reported thanactive ones: passive strategies such as taking medication (47%), resting (31.5%), and

using hot/cold packs (23.4%) were most commonly reported, while the most commonlyreported active strategy was exercising (25.8%). Only 33.5% of those who used active

behavioural and/or cognitive strategies used them exclusively, while 67.7% of thosewho used passive behavioural and/or conventional medical strategies did soexclusively. Self-management strategies were associated with both pain-related

disability and use of health services in multiple logistic regression models. Usingpassive strategies increased the likelihood of having high levels of pain-related

disability (adjusted OR 2.59) and more pain-related health care visits (adjusted OR

2.9); using active strategies substantially reduced the likelihood of having high levels ofpain-related disability (adjusted OR 0.2). In conclusion, we have shown in a

population-based study that clinical findings regarding self-management strategiesapply to the broader population and advocate that more attention be given tocommunity-based strategies for improving awareness and uptake of active self-

management strategies for chronic pain.

Keywords: Self-care; Chronic pain; Epidemiology

Pain (2005) 113, 285-292

Also see the following investigations into the role of neuro-immune substances in pain

modulation

Tumor necrosis factor a and interleukin-1 stimulate the expression of cyclooxygenase

II but do not alter prostaglandin E 2 receptor mRNA levels in cultured dorsal rootganglia cells

Jill C. Fehrenbacher, Thomas H. Burkey, Grant D. Nicol and Michael R. Vasko

Department of Pharmacology and Toxicology, Indiana University School of Medicine,Medical Science Bldg-MS A401, 635 Barnhill Drive, Indianapolis, IN 46202, USA

Received 3 July 2004; revised 15 September 2004; accepted 28 September 2004. .Available online 11 November 2004.

Abstract




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Tumor necrosis factor a (TNFa) and interleukin 1 (IL-1) are pro-inflammatory

cytokines capable of altering the sensitivity of sensory neurons. Because sensitizationelicited by IL-1 and TNFa is blocked by inhibition of the inducible enzyme,cyclooxygenase-II (COX-2), we examined whether these cytokines could increase

COX-2 expression in dorsal root ganglion (DRG) cultures. Treatment of cell cultureswith either IL-1 or TNFa increases immunoreactive COX-2, as measured by

immunoblotting, in a time- and concentration-dependent manner. A 24-h pretreatmentwith 10 ng/ml IL-1 or 50 ng/ml TNFa augmented COX-2 expression 50- and 8-foldover basal levels, respectively. Immunohistochemistry established the presence of

COX-2-like immunoreactivity in both neuronal and non-neuronal cells in culture. Theaddition of IL-1 receptor antagonist blocked the induction of COX-2 expression by IL-

1, but did not alter TNFa-stimulated increases in COX-2, indicating that themechanism of TNFa is not limited to increasing the expression of IL-1. The basal andTNFa-induced expression of COX-2 was not dependent on the presence of NGF in the

growth media. IL-1 and TNFa treatment for 24 h enhanced prostaglandin E 2 (PGE 2 )production 24-fold, which was blocked by pretreatment with the COX-2 inhibitor,

NS-398. Exposing cultures to PGE 2 , IL-1, or TNFa for 24 h did not alter PGE 2receptor (EP) mRNA levels. These results indicate that TNFa and IL-1 induce the

functional expression of COX-2 but not EP receptors in DRG cells in culture andsuggest that cytokine-induced sensitization of sensory neurons is secondary toprostaglandin production and not alterations in EP receptors.

Link to article at on-line Pain journal at Elsevier.com

Excitatory and modulatory effects of inflammatory cytokines and neurotrophins

on mechanosensitive group IV muscle afferents in the rat

Ulrich Hoheisel b, Thomas Unger b and Siegfried Mense a,

a Institut fr Anatomie und Zellbiologie, Universitt Heidelberg, Im Neuenheimer Feld307, D-69120 Heidelberg, Germanyb Institut fr Pharmakologie und Toxikologie, Charit, Humboldt Universitt,

Dorotheenstrae 94, D-10117 Berlin, Germany

Received 16 June 2004; revised 22 October 2004; accepted 13 December 2004. AIB-400013. Available online 1 February 2005.

Abstract

In inflamed tissue including skeletal muscle the concentrations of cytokines andneurotrophins are known to increase. However, nothing is known about a possible

contribution of these agents to muscle pain and hyperalgesia. The present studyinvestigated acute effects of cytokines and neurotrophins on response properties ofslowly conducting muscle afferents. In anaesthetised rats, the impulse activity of single

mechanosensitive group IV fibres innervating the gastrocnemiussoleus muscle wasrecorded and tumour necrosis factor-a (TNF-a), interleukin-6 (IL-6), nerve growthfactor (NGF), or brain-derived neurotrophic factor (BDNF) were injected into the

muscle. Changes in the mechanosensibility of the endings following administration of




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the agents were tested with repeated pressure stimuli of defined forces. A low

mechanical threshold in the innocuous range was found in 44.4% of the units tested,55.6% required strong, potentially tissue-damaging pressure stimuli for activation.NGF excited only units that had a high mechanical threshold, while IL-6 was a

stimulant for low-threshold mechanosensitive units only. TNF-a and BDNF did notexcite group IV units but had a desensitising action: after TNF-a or BDNF, the

response magnitudes to pressure stimuli decreased significantly. The data indicate thatcytokines and neurotrophins influence the impulse activity and mechanosensitivity ofgroup IV muscle afferent units. These effects could be of functional significance when

the agents are released from muscle cells under pathophysiological circumstances.

Keywords: Group IV afferent units; Skeletal muscle; Cytokines; Neurotrophins;

Nociception

Link to Pain Journal

Spinal nerve lesion-induced mechanoallodynia and adrenergic sprouting in

sensory ganglia are attenuated in interleukin-6 knockout mice

Matt S. Ramera, Patricia G. Murphy b, Peter M. Richardson b and Mark A. Bisby a

a Department of Physiology, Queen's University, Kingston, Ontario, K7L 3N6 Canada

b Division of Neurosurgery, McGill University and Montreal General Hospital,Montreal, Quebec, H3G 1A4 Canada

Received 24 March 1998; revised 25 June 1998; accepted 1 July 1998. Availableonline 20 November 1998.

Abstract

Tight ligation and transection of the L5 spinal nerve (SNL) gives rise to pain which isdependent upon activity in the sympathetic nervous system. It also results in novel

adrenergic sympathetic innervation of the dorsal root ganglion (DRG) with theformation of pericellular axonal basket structures around some DRG neurons. Since thesympathetic sprouting and basket formation may represent an anatomical basis for

pain-generating interactions between the sympathetic efferent neurons and sensoryafferent neurons, it is of great interest to determine possible chemical mediators of this

phenomenon. Previous findings have shown that IL-6 can contribute tosympathetically-independent pain, and can give rise to thermal hyperalgesia when

injected intrathecally. We have now investigated a possible contributory role of thepleiotropic cytokine interleukin-6 (IL-6) in sympathetically-mediated pain: we gaveIL-6 knockout mice and mice of the parent strain c57B6/129 a SNL, assessed their

resulting pain behavior for 10 days post-surgery, and used tyrosine-hydroxylaseimmunohistochemistry to compare sympathetic sprouting in the DRG at the end of thetesting period. We found that thermal allodynia (as assessed by measuring the latency

to withdrawal from radiant heat) did not differ significantly between strains. On theother hand, in the IL-6 mice, mechanoallodynia (as assessed with von Frey filaments)

was markedly delayed. Sympathetic invasion of the fiber tract and cell layer of the




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DRG, and the formation of pericellular axonal baskets were all significantly reduced in

the IL-6 knockout mice compared to the control strain. These results imply afacilitatory role for IL-6 in pain and sympathetic sprouting induced by nerve injury, andadd to the growing list of roles for IL-6 in neuropathological events.

Author Keywords: Sympathetic sprouting; Allodynia; Hyperalgesia; DRG; Cytokines;Mice

Index Terms: spinal nerve; nerve injury; allodynia; hyperalgesia; interleukin 6

link to Pain Journal

Neurophysiology of Pain and Inflammation

Clinical example using mechanical traction

Presentation on Stress, Exercise and the Immune System

Mechanical traction neurophysiology conceptualised and conceivedpredominantly during early 1995 as part of my Masters treatise at SydneyUniversity - for references see below as well as the paper on pain and

inflammation elsewhere on this site.

Melzack R (1999) From the gate to the neuromatrix. Pain Supplementation 6; S121-

S126

Newport DJ, Nemeroff CB (2000) Neurobiology of post traumatic stress disorder.Current Opinion in Neurobiology 10; 211-218

Goldstein JA (2004) Tuning the Brain. Principles and practice of neurosomatic

medicine. The Hawthorn Press New York

Grossberg S (2000). The complimentary brain: unifying brain dynamics and

modularity. Trends in Cognitive Sciences 4, 233-246

The Dorsal Root Ganglion, the Intervertebral Foramen and

Musculoskeletal Physiotherapy

by Martin Krause, 1995 & 2000.

SUMMARY

The efficacy of manual therapy interventions has been extensively criticised in recent

years. Serious charges of physiotherapy induced conviction of disease (nocebo) leading

to chronicity have been raised. Paradoxically, the omission of higher centre processing

in the design of double blind investigations, results in a dichotomy of interpretation




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which, either justifies the determination of inefficacy or alternatively, predicts an

important role for higher centre involvement during the selection and application of

manual therapy techniques. Specifically, the sensory-discriminative and motivational-

affective responses require dissemination if hypotheses regarding the efficacy of

manual therapy treatment, for acute radicular pain, are to be made. Currently, the

majority of pain research has established immune-nervous system responses associated

with post-traumatic inflammation rather than repair. Recently, dysfunction of the dorsal

root ganglion (DRG), which lies in the intervertebral foramen (IVF), has been

implicated in both the genesis and chronicity of radicular pain. Previously, manual

therapy techniques to the IVF, such as traction, have been anecdotally advocated to

normalise signs and symptoms in acute radicular pain. Clinicians use the presenting

signs and symptoms, to guide their clinical reasoning processes. Additionally, the

normalisation of signs and symptoms is used to demonstrate the usefulness of a

treatment technique to their clients. Investigations demonstrate higher centre

involvement in the reduction of pain and inflammation. Clearly, if the efficacy of

manual therapy is to be determined, then the differentiation between a treatment

dependent descending inhibition of pain and inflammation, with that of aplacebo or

nocebo, is required.




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INTRODUCTION: HIGHER CENTRE SENSORY-DISCRIMINATIVE ANDMOTIVATIONAL-AFFECTIVE SENSORY PROCESSING BY THE NERVOUSSYSTEM




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Recently, sensory-discriminative (Ploner et al. 1999) and motivational-affective (Vogt

et al 1993) pathways for pain have been demonstrated in humans. The mainconstituents of the sensory-discriminative aspects of pain (A fibre activity) include thelateral thalamic, primary (I) and secondary (II) somatosensory cortices. Conversely, the

motivational affective aspects of pain consists predominantly of the medial thalamicnuclei and the anterior cingulate cortex. Importantly, this structural differentiation

suggests that the specificity of treatment and the demonstration of efficacy areimportant aspects in the nervous systems responses to treatment. Frequently, thepractitioner uses the normalisation of signs and symptoms to demonstrate efficacy, in

addition to guiding their clinical reasoning processes (Higgs & Jones 1995). However,such an approach could be dangerous as it reinforces the conviction of disease and

could result in a nocebo effect (Bogduk 1997; Cohen 1995). Hence, what role does thesensory-discriminative aspect of pain have on the motivational-affective response tomanual therapy techniques?

Positron Emission Tomography (PET) has demonstrated that higher centres of thenervous system may be actively involved in, the descending inhibition of acute pain

and inflammation in humans (Hsieh et al. 1995; Petrovic et al. 1999). Animal

investigations of supraspinal opioids found a block in the perception of pain, through a64% reduction in superficial laminae dorsal horn activity (Gogas et al. (1991) (usually

associated with a predominance of nociceptive specific neurones {Lima et al. 1994}),and a 85% reduction in ventral horn activity (usually associated with motor neurones)in animals (Schomburg & Steffens 1991). One source of descending inhibition involves

pontine noradrenergic projections, in animals (Janig 1985; Martin et al. 1999; Post etal. 1986; Morgan et al. 1989; Nakagawa et al. 1990; Ren et al. 1990; Proudfit 1992).

Although descending noradrenergic inhibition is considered to be an opioid-independent form of analgesia (Proudfit 1992), evidence supports the view that

P-opioid and D-2 noradrenergic receptors are functionally linked to pain modulation

(Gebhart et al 1994). Higher centres have been implicated in sympathetic responses, to

spinal manual therapy techniques, in humans (Petersen et al. 1993; Vicenzino et al.1998). Plausibly, the sensory-discriminative pathway was involved in the reduction of

secondary hyperalgesia, as these techniques were applied to the neck for lateral elbowpain.

Evidence for important motivational-affective responses are from animal investigationswhich, substantiate the finding that higher centres can act in an antinociceptive manner(Sandkuehler et al. 1995). Importantly, a "behavioural set" has been defined as 'a state

of readiness or preparation to receive a stimulus that has not yet arrived, or a state ofreadiness or preparation to make a movement' (Woodworth 1958 c.f. Dubner & Ken

1999). Therefore, the net effect of descending inhibition in animals from the Locus

Coeruleus/Subcoeruleus, Nucleus Raphe Magnus, and Nucleus Gigantocellularis is to"dampen or counteract the cascade of events that ultimately lead to the development of

inflammatory hyperalgesia" (Dubner and Ken 1999) (see figure 1). Attention andcognitive factors such as previous experience of manual therapy or possibly even the

apparent normalisation of signs and symptoms could modulate noxious stimuli in theprimary somatosensory cortex (Bushnell et al. 1999; Dubner & Ken 1999). Thesemotivational-affective responses presumably occur with the interaction of the client and

the therapist during the clinical reasoning process.




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Together, these investigations represent very powerful arguments for assessment of the

signs and symptoms during the clinical reasoning process, thereby involving highercentres in the neuromodulation of pain and inflammation. Additionally, the activationof higher centres through the re-setting of stabilising muscles, after the person receives

passive joint mobilisation treatment, may be necessary for even greater involvement ofhigher centres. Confirmation of motivational-affective responses to treatment would

require the use of psychometric pain questionnaires, positron emission tomography(PET) and functional MRI to demonstrate the temporal changes in cerebral activity(Casey & Minoshima 1997; Svensson et al. 1997) before, during and after treatment

ECTOPIC IMPULSE GENERATION IN THE DORSAL ROOT GANGLION(DRG) AND NEUROGENIC INFLAMMATION IN THE SENSORY NERVE

ENDINGS OF THE SINUVERTEBRAL (SNV) NERVE A ROLE FOR

LOCALISATION OF TREATMENT?

To justify an important localised sensory-discriminative response to injury and hencetreatment requires an appreciation of dorsal root ganglion (DRG) dysfunction. Inflamed

structures demonstrate increased excitability of sensory nerve endings (Raja et al. 1988;Schmidt et al. 1994). A cause of acute radicular spinal pain may be the generation ofexcessive electrical activity (ectopic impulses) from inflamed structures. Passive joint

mobilisations may be useful in the treatment of radicular spinal pain by 'unloading'those structures (e.g. DRG) whose functions include the modulation of ectopic impulse

generation. Ectopic discharge can occur in the DRG following damage that occursdistally in the neural pathway and in the presence of endoneural oedema in animals(Howe et al. 1977), and humans (Nordin et al. 1984). Essentially, endoneural oedema

of the DRG resulting from compression by extraneural inflammatory exudate (Chataniet al. 1995) in the intervertebral foramen (IVF) generates ectopic electrical impulses

(Bandalamente et al. 1987). These ectopic impulses originating in the DRG are thoughtto propagate into the spinal cord and into peripheral receptor sites (Wall & Devor 1983;Bandalamente et al. 1987). Consequently, the extent of spinal cord sensitisation,

oedema and neurogenic inflammation may in some cases be more significant than thephysical size of an intervertebral disc (IVD) protrusion (Garfin et al. 1991; Thelander et

al. 1992). Interestingly, Bogduk (1997) advocates radiofrequency neurotomy in thetreatment of chronic spinal pain. However, in acute radicular pain it becomes apparentthat the DRG is likely to regulate the excitability of the sensory nerve endings (Devor

1999). Therefore, 'unloading' of mechanical compromise (extraneural inflammation)around the DRG in the IVF, by for example traction, could plausibly reduce ectopic

impulse generation (see figure 2).

Ectopic impulse generation from the DRG may propagate throughout the innervation of

the sinuvertebral (SNV) nerve. The SNV nerve is a peripheral nerve formed by therecurrent branch of the ventral ramus and a branch of the grey ramus communicantes ofthe somatic and peripheral sympathetic nervous systems respectively (Bogduk &

Twomey 1997). Since the SNV nerve does not innervate superficial structures of thebody, it may play a sensory-discriminative role such as mechanoception andnociception (Ahmed et al. 1993). Certainly, the types of receptors innervating the

ligamentous structures, suggests such roles (Korkula et al. 1985; Weinstein et al.1988a). Similar to other peripheral nerves, a vasoactive role on blood vessels may be afunction of the sympathetic component of the SNV nerve (Appenzeller et al. 1984;




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Selander et al. 1985; Weinstein et al. 1988b; Zochodne et al. 1990). Importantly, the

terminals of the SNV nerve appear anatomically well placed to transmit ectopicimpulses to the IVD, posterior longitudinal ligament, Hoffman ligaments, and the duramater (Weinstein et al. 1988a, Bogduk & Twomey 1997). This increased ectopic

impulse propagation increases neurogenic inflammation, possibly at the SNV nervereceptor sites (Markowitz et al. 1989; Xavier et al. 1990; Chatani et al. 1995).

Arborization of the SNV nerve terminals can cause neurogenic inflammation in anexpanded receptive field (LaMotte et al. 1991). Furthermore, expansion of spinal cordneuronal hypersensitivity may arise from the propagation of ectopic impulses into the

spinal cord from the periphery (Wall & Devor 1983). This expansion is calledsecondary hyperalgesia and possibly explains the severity of referred limb pain, which

is a frequent manifestation of radicular pain. Therefore, a dual role of the SNV nerve inthe detection of nociception, in addition to the propagation of ectopic impulses tostructures of the IVF and spinal canal is plausible. Presumably, specific manual therapy

techniques will induce a sensory-discriminative response, which is likely to activate amotivational-affective response that either increases or decreases secondary

hyperalgesia depending upon the perceived appropriateness of the treatment.

THE HYPOTHESIS: SPINAL TECHNIQUES AFFECT THE DORSAL ROOT

GANGLION (DRG) IN THE INTERVERTEBRAL FORAMEN (IVF)

Clearly the expansion of the hypersensitive receptive field, underlie the importance of

investigating the sensory-discriminative aspects of treatment techniques. Variation oftechniques to the IVF, such as the type of load (stretch vs. compression, active vs.passive), the position, and the duration are probably detected by SNV nerve terminals,

innervating inflamed structures. Since the SNV nerve appears to innervate the DRGitself (Cuartico et al. 1988; Groen et al. 1988), the ramifications of extraneural

inflammation in the IVF are vascular compromise inducing intraneural oedema in theDRG. Consequently, intraneural oedema causes ectopic impulse generation, whichincreases the intensity of the existing extraneural neurogenic inflammation. Hence, an

ongoing self-perpetuating cycle of neurogenic inflammation ensues, which potentiallyimpoverishes any regulation in excitability of sensory nerve endings by the DRG. Thus,

if a treatment technique affects the vascular compromise (and extraneuralinflammation) surrounding the DRG, in the IVF, then a resultant reduction inendoneural oedema in the DRG would interrupt this self-perpetuating cycle of

neurogenic inflammation. Significantly, reduced ectopic impulse generation andenhanced modulation of excitability of sensory nerve endings, by the DRG, may

substantiate the validity of using the immediate normalisation of signs and symptomsfor the determination of the appropriate technique (Larsson et al. 1980; Maitland 1986;Eggertz 1986; Pal et al. 1986; Knutsson et al. 1988) (see figure 3). Thus, any measured

changes in sensory-discriminative function may imply an activation of higher centreresponses. In turn, the subsequent motivational-affective response may be indirectly

determined through autonomic testing of that innervation field (Sandroni 1998).

A MODEL: MECHANICAL TRACTION FOR THE NORMALISATION OF

SIGNS AND SYMPTOMS IN ACUTE RADICULAR SPINAL PAIN




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A recent review suggested some people with acute radicular spinal pain responded well

to traction with the normalisation of signs and symptoms (Krause et al. 2000).Specifically, to determine an important sensory-discriminative response then thepredictive validity of the current model is the normalisation of signs and symptoms

within a narrow band of loading tolerance. Since the valid dose of traction would be thenormalisation of signs and symptoms, then the inappropriate dose will be the

deterioration of signs and symptoms. In considering ectopic impulse generation,'unloading' of the contents of the IVF (i.e. Nerve Root/Dorsal Root Ganglion/SpinalNerve, intra-foraminal blood vessels, sinuvertebral nerve) may be a logical explanation

for the first observation of the normalisation of signs and symptoms. Reduction inectopic impulse generation and simultaneously enhanced modulation of inflammation

could be expected from the mechanical 'unloading' of the DRG in particular. Similarly,if the inflamed structures comprising the IVF (i.e. IVD, Zygapophyseal joint,Hoffman ligaments, etc) (Groen et al. 1988; Park & Watanabe 1990; Wiltse et al. 1993;

Bogduk & Twomey 1997) are 'overloaded', then ectopic impulse generation (Raja et al.1988; Schmidt et al. 1994) with the deterioration of signs and symptoms can be

expected during excessive traction. The normalisation-deterioration of signs andsymptoms can be referred to as a two-thresholdhypothesis.

The clinical implications of the sensory-discriminative and motivational-affective

aspects of pain highlight the importance of differentiating a specific neurophysiologicaleffect from theplacebo and nocebo. Clearly the demonstration of efficacy andexpectations of outcome are an essential aspect of any treatment protocol. Presumably,

some people will deteriorate or not respond to traction at all. In these people, theloading threshold has not been reached or another form of treatment is more

appropriate. Importantly, lack of improvement or deterioration may induce a noceboresponse. Therefore, the clinical reasoning process needs to identify the respondersfrom the non-responders in a manner, which expedites appropriate treatment. Hence, a

correlation with psychometric questionnaires and the temporal aspects of functional

MRI and PET diagnostic imaging would be required before conclusions of efficacy aredrawn. Since it is unlikely that a person could guess their threshold for theirnormalisation of signs and symptoms, then a method of investigation for adifferentiation of the neurophysiological,placebo and nocebo effect may include the

use of the two-thresholdhypothesis.




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THE VALIDITY OF USING THE NORMALISATION OF SIGNS AND

SYMPTOMS

The validity of testing procedures underlie the ability of the examiner to make a clinical

prediction (Payton 1988). Clinical reasoning uses signs and symptoms to determine theappropriateness of a treatment strategy (Higgs & Jones 1995). However, is thereduction in ectopic impulse generation and the modulation of excitability in sensory

nerve endings correlated with the observable normalisation of signs and symptoms?Significantly, the incidence of the normalisation of signs and symptoms is not clear.

Therefore, is the normalisation of signs and symptoms useful for making consistentdecisions on the appropriateness of treatment technique for acute radicular pain?Finally, does the use of this methodology impart conviction of disease?

The pain response and range of motion (ROM) of straight leg raise (SLR) is a variableused to assess the effects of treatment using traction (Larsson et al. 1980; Eggertz 1986;

Mathews et al. 1987; Pal et al. 1986; Tesio et al. 1989). The load and position of thepatient have been defined by the improvement in the pain free ROM of SLR (Larssonet al. 1980). During SLR, the direct contact pressure of the DRG against the structures

of the IVF (Smith et al. 1993) and tension generated in inflamed nerve roots arethought to cause sufficient ectopic impulse generation to stimulate the reflexogenic

drive to the alpha-motor neurones, as demonstrated in animals (Woolf et al. 1994).Clinically, this reflexogenic drive may represent increased muscle activity that reducesROM. Since ectopic impulse generation from the DRG also propagates into the spinal

cord, then neuronal hypersensitivity could explain alterations in signs and symptoms onthe contralateral side seen in humans and animals (Larsson et al. 1980; Woolf 1984;

Woolf & Swett 1984; Woolf & MacMahon 1985; Woolf & Wall 1986b; Schmidt 1990;Eckert et al. 1999). Confirmation of such findings require, fine needleelectromyography (EMG). Obviously, solely comparing ROM of SLR to the opposite

side without due consideration of other variables may lead to errors in the clinical

reasoning process.

Other variables inferring some validity when correlated with the normalisation of SLR,during treatment, include reduction in pain intensity, normalisation of muscle strength,and restoration of somatosensory evoked potentials (Knutsson et al. 1988).

Additionally, improved asymmetric skin temperatures and sensation testing has beendemonstrated (Knutsson et al. 1988; Onel et al. 1989). Although, the incidence of thenormalisation of signs and symptoms was high, methodological problems exist which

suggest caution in the interpretation of these results. Never the less, normalisation ofmuscle power, skin sensation, skin temperature, and pain intensity may be correlated

with ROM of SLR to predict appropriate technique during the clinical reasoning

process.

Normalisation of tendon reflexes has been used to assess patients, during auto-traction,

and is thought to correlate with the normalisation of conduction along nerve fibres(Larsson et al. 1980; Pal et al. 1986; Knutsson et al. 1988; Onel et al. 1989; Sabbahi &

Khalil 1990b). However, hypersensitivity in spinal cord reflexes can cause tendonreflexes to increase or decrease during neurogenic inflammation and ectopic impulsegeneration (Ferrell et al. 1988; Rees et al. 1994). Evidence for variable hyper- and

hyporeflexia during inflammation comes from Hoffman-reflex investigations where




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increasing stimulus intensity increases the reflex until a given stimulus threshold is

reached where a decrease or complete block in the Hoffman-reflex amplitude occurs(Sabbahi & Khalil 1990a). Since inflamed tissues have reduced receptor threshold, thenexcessive electrical activity during loading may alter reflex activity (Raja et al. 1988).

Whether the hypersensitivity of spinal cord reflexes from neurogenic inflammation andectopic impulse generation represent a decrease rather than an increase in tendon reflex

awaits confirmation in the clinical situation. Importantly, this stimulus-dependentphenomenon may explain the deterioration of signs and symptoms when a technique isapplied indiscriminately. Paradoxically, rather than demonstrating efficacy, such

sensory-discriminative methodology has been seen to impart conviction of disease,which negatively influences the motivational-affective aspects of the pain (Bogduk

1997: Cohen 1995, Zusman 1998). Therefore, clinical reasoning based upon thenormalisation of signs and symptoms would only be justified if a reduction inchronicity could be demonstrated. Epidemiology, using large numbers of subjects,

would be required to validate these opinions.

RESTORATION OF NERVE CONDUCTION THROUGH THE MODULATION

OF NEUROGENIC INFLAMMATION AND CYTOKINE-IMMUNERESPONSES BY THE DRG AND PERIPHERAL SYMPATHETIC NERVOUS

SYSTEM (SNS)

Peripheral nerve injury results in morphological changes in the DRG (Dib-Hajj et al.

1999; Eckert et al. 1999; Ramer et al. 1999). Although these morphological changesrelate to chronic constriction, the onset and perpetuation of neurogenic inflammatoryresponses appear to begin within hours of the acute phase of injury (Schmidt et al.

1994). Notably, the SNV nerve and spinal nerve may represent the peripheral nervessusceptible to constriction irritation. The proposed genesis of these morphological

changes are Wallerian degeneration in the periphery releasing nerve growth factor,leukaemia inhibitory factor and Interleukin (IL) - 6 (Ramer et al. 1999). The activationof similar cytokines is also associated with immune responses during exercise induced

musculoskeletal damage (Pedersen et al. 1999) (SEE : Immune function and musclemass orslide presentation for more detail). The disruption of the fibroblast endothelium

is considered the 'trigger' for the release of tumour necrosis factor, IL-1, IL-6, IL-8.Subsequently, there is an activation of prostaglandin driven release of Substance P,with its consequential further release of cytokines from macrophages and mast cells,

which completes a self-perpetuating cycle of inflammation (Groenblad et al. 1991;Rothwell & Hopkins 1995). Generally, inflammation and mast cell degranulation

affects blood-nerve permeability and nerve conduction (Harvey et al. 1994). If, theinteraction between the DRG and peripheral SNS is responsible for these immuneresponses during inflammation, then a treatment technique like traction may aid in

reducing constriction of the affected peripheral nerves. In turn, the re-establishment ofDRG function will enhance the modulation of cytokine activity. It is difficult to

conceive any methodology, which may directly image these morphological changes inhumans. Interestingly, some of the resultant restitution of nerve conduction is predictedto occur beyond the immediate application of the treatment technique. Therefore, the

extent by which manual therapy techniques can prevent such morphological changesfrom occurring could justify early and appropriate treatment interventions. Certainly,pharmacological investigations have demonstrated greater treatment efficacy when

early intervention was instigated (Bhala et al. 1988).




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REDUCTION OF VENOUS CONGESTION AND THE MODULATION OF

HOMEOSTASIS BY THE DRG IN THE INTERVERTEBRAL FORAMEN(IVF).

Reduction in mechanical irritation from venous congestion around the DRG may be anexplanation for the efficacy of a treatment technique such as traction. Cadaveric studiesdemonstrate that mechanical abnormalities within the spine, such as IVD extrusion,

result in dilatation, congestion, and thrombosus of veins contributing to disruption ofthe vascular endothelium and consequent fibrin deposition (Hoyland et al. 1989).

Importantly, intraforaminal blood flow may represent part of the sensory-discriminativefunction of the DRG. The unusual location of the DRG between the peripheral andcentral nervous systems has been related to its hypothesised function as a sensor of

background information such as homeostasis of the IVF milieu (Devor 1999). Besideslocation, evidence supporting a homeostatic function of the DRG is the lack of blood-

nerve barrier around the cells of the DRG and the highly convoluted nature of itsvasculature (Devor 1999). Obviously, sufficient blood flow would be required to detecthomeostasis. Arguably, techniques such as traction achieve reduction in mechanical

irritation by increasing the space for the intra-foraminal blood vessels of the IVF.Apparently, improved IVF space has been demonstrated by merely positioning a person

to reduce their lumbar lordosis (Panjabi et al. 1983). The implications are that thefunction of the DRG may be susceptible to vascular and mechanical compromise in theIVF. Since venous pressure is quite low, the advocacy of using positions of comfort in

acute radicular pain may be justified (Maitland 1986), as the required restitution ofhomeostasis in the IVF may occur.

Additional explanations for the effectiveness of using the 'positions of comfort' or lowdose traction reside in the effect of neural irritation from compression at two locations.Besides swelling in the IVF from inflammatory exudate, the zygapophyseal (Z) joint

may be swollen and inflamed. Histological changes suggestive of inflammation have

been demonstrated in the Z-joint (Cooper et al. 1995). Since the Z-joint represents theposterior aspect of the IVF then presumably some decompression of the IVF may resultfrom stretching of the Z-joint capsule during traction (Krause et al. 2000). Interestingly,nutrient transport to the nerve roots from both the intraneural blood vessels and from

diffusion from the cerebrospinal fluid is affected in the intermediate zone between thetwo sites of compression almost as much as at the compression sites themselves, in rats.Even low pressure (10mmHg) is sufficient to induce a significant reduction in total

blood flow possibly from retrograde capillary stasis due to venous occlusion (Rydeviket al. 1984a,b; Olmarker et al. 1989a,b; Cornefjord et al. 1992; Matsui et al. 1992;

Takahashi et al. 1993). Clinically, pressure from extruded IVD material, in the IVF,and swelling of the Z-joint may represent a similar situation to the animal model.

Importantly, relatively small traction loads or 'positions of comfort' may be required toreduce compromise at one site, thus resulting in the restoration of venous flownecessary for any homeostatic function of the DRG in the IVF. Perhaps, ultrasound

imaging may be useful for demonstrating alterations in the dimensions of the Z-jointcapsule. Certainly, ultrasound has been effective in demonstrating changes to the sizeor shape of the multifidus muscle which inserts into the Z-joint capsule (Hides et al.

1994). MRI of the IVF, doppler ultrasound of intraforaminal flow and computermodelling may be investigative procedures, of the future, for determining the

biomechanical response to the treatment technique.




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HEALING: THE ROLE OF THE VASCULATURE AND PERIPHERAL

SYMPATHETIC NERVOUS SYSTEM IN THE MODULATION OFNEUROGENIC INFLAMMATION AT THE SINUVERTEBRAL (SNV) NERVETERMINALS: A MOTIVATIONAL AFFECTIVE RESPONSE TO

SOMATOSENSORY STIMULI?

The sympathetic efferents are postulated to be important to the healing process since

the activation of peripheral terminals of sympathetic postganglionic neuronescontributes to neurogenic inflammation (Levine et al. 1986). Since emotions and

somatosensory inputs profoundly influence the autonomic nervous system, non-invasive autonomic testing has been advocated in people with pain (Sandroni 1998).Sympathetic postganglionic neurones release inflammatory mediators that increase

plasma extravasation, including prostaglandins (Coderre et al. 1989; Gonzales et al.1989; Gonzales et al. 1991; Green et al. 1991a,b). Additionally, under conditions of

sympathetic postganglionic neuronal modulation, bradykinin has been found toincrease plasma extravasation (Green et al. 1992). Importantly, the interaction betweenprimary afferent nociceptors (associated with the DRG) and sympathetic efferents

during inflammation appears to be increased for intact nociceptors with axonstravelling in damaged nerve (Sato & Perl 1991). Conversely, the sympathetic

postganglionic neurones also release mediators, which decrease plasma extravasation,including neuropeptide Y and noradrenaline (Green et al. 1991; 1992). Apart frommodulating plasma extravasation these substances may also interact with endothelial

relaxing factor (Greenberg et al. 1991) and platelet-activating factor (Heller et al. 1994)in the blood vessels. Significantly, agents that enhance synovial plasma extravasation

have been demonstrated to decrease tissue injury during inflammation (Coderre et al.1991). The mechanisms by which sympathetic nerves decrease tissue injury areunclear. However, an increased plasma extravasation would be expected to reduce the

concentration of inflammatory substances through the facilitation of venous drainagethereby improving healing (Heller et al. 1994) at the terminals of the SNV nerve. These

animal investigations suggest that in addition to non-invasive autonomic testing, themotivational-affective responses need to be monitored using psychometric painquestionnaires.

DURATION OF EFFICACY: THE 'SILENCING' OF ECTOPIC IMPULSEGENERATORS COULD LEAD TO A PROLONGED EFFECT SIMILAR TO

LOCAL ANAESTHETICS.

The relief of pressure from extraneural inflammatory compromise at SNV nerve

receptor sites surrounding the DRG could 'silence' ectopic impulse discharges. Ideally,

this 'silencing' would last for a similar duration to that demonstrated by localanaesthetics. Local anaesthetics 'silence' the neurones at the site of ectopic impulsegeneration for a period outlasting the pharmacological effect of the local anaesthetic(Devor et al. 1992). It has been hypothesised that any silencing of ectopic discharges

should allow the autoinhibitory interneurones of the spinal cord to recover from theneurotoxic effects of increased large diameter afferent bombardment (Sugimoto et al.

1990; Dubner 1991). Alternatively, this 'silencing' may provide the sensory-discriminative pathway an opportunity to activate powerful descending inhibition ofpain and inflammation. A reduction in ectopic discharge has been shown in cats when

the compression stimulus was removed (Howe et al. 1977). Thus, if a technique




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reduces endoneurial oedema by assisting in the removal of extraneural inflammatory

exudate from around the DRG and SNV nerve, then this may explain any normalisationof neurological signs and symptoms for a duration outlasting the period of thetechnique. Importantly, the demonstration of such temporal responses, once the

biomechanical stimuli of our techniques has been removed, would highlight theoverwhelming influence of the neurophysiological processes in healing.

CONCLUSION

Reduced mechanical irritation of the DRG in the IVF may be responsible for theimmediate and long lasting effects of the appropriate treatment for acute radicular pain,in some people. Consequently, reduced ectopic impulse generation and enhanced

modulation of pain and inflammation should be accompanied by the normalisation ofsigns and symptoms. Sensory-discriminative and motivational-affective nervous system

responses are likely mechanisms required for the prolonged normalisation of signs andsymptoms. Clearly, future investigations into the efficacy of manual therapy, requiresthe incorporation of higher centre processing into the methodology. Vascular changes

as a result of inflammation are probably modulated by the sympathetic nervous system(SNS). Improved blood flow allows the restoration of the homeostatic function of theDRG. Additionally, the modulation of the excitability of sensory nerve terminals, by

the DRG, involves its interaction with the SNS. Enhanced modulation of prostaglandinactivity through the interaction of the DRG and SNS with the cytokine-immune system

at the sites of innervation of the SNV nerve may restore nerve conduction. The two-thresholdhypothesis for the dose of traction could represent a novel experimentalmethod, as it is unlikely that a person can guess the threshold of their normalisation of

signs and symptoms. A promising investigative model, using the dose of traction,psychometric analysis, computer modelling, in addition to diagnostic imaging,

represents a potential methodology for unravelling the mysteries of radicular pain. Theeffect of appropriate early intervention to the incidence of chronicity requiresinvestigation, since the validity and precise incidence of the normalisation of signs and

symptoms during the treatment of acute radicular pain has not been clearly established.Hereby, charges of physiotherapy induced conviction of disease leading to chronicity

can be addressed.

all intellectual property rights should be observed; written

predominantly in early 1995 as part of my Masters in Applied Science(Manipulative Physiotherapy)

uploaded by Martin Krause 2000




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Descending modulation of pain hypothesis vindicated by recentresearch:

Skyba DA, Radhakrishnan R, Rohlwing JJ, Wright A, Sluka KA (2003) Joint

manipulation reduces hyperalgesia by activation of monoamine receptors but notopioid or GABA receptors in the spinal cord. Pain, 106, 159-168

Ren & Dubner (2002). Descending Modulation of Pain: Pain, 100, 1-6

see also

Tumor necrosis factor and interleukin-1 stimulate the expression of cyclooxygenase

II but do not alter prostaglandin E2 receptor mRNA levels in cultured dorsal root

ganglia cells

Jill C. Fehrenbacher, Thomas H. Burkey, Grant D. Nicol and Michael R. Vasko

Department of Pharmacology and Toxicology, Indiana University School of Medicine,Medical Science Bldg-MS A401, 635 Barnhill Drive, Indianapolis, IN 46202, USA

Received 3 July 2004; revised 15 September 2004; accepted 28 September 2004. .Available online 11 November 2004.

Abstract

Tumor necrosis factor (TNF) and interleukin 1 (IL-1) are pro-inflammatorycytokines capable of altering the sensitivity of sensory neurons. Because sensitization

elicited by IL-1 and TNF is blocked by inhibition of the inducible enzyme,

cyclooxygenase-II (COX-2), we examined whether these cytokines could increaseCOX-2 expression in dorsal root ganglion (DRG) cultures. Treatment of cell cultureswith either IL-1 or TNF increases immunoreactive COX-2, as measured byimmunoblotting, in a time- and concentration-dependent manner. A 24-h pretreatment

with 10 ng/ml IL-1 or 50 ng/ml TNF augmented COX-2 expression 50- and 8-foldover basal levels, respectively. Immunohistochemistry established the presence of

COX-2-like immunoreactivity in both neuronal and non-neuronal cells in culture. Theaddition of IL-1 receptor antagonist blocked the induction of COX-2 expression by IL-1, but did not alter TNF-stimulated increases in COX-2, indicating that the

mechanism of TNF is not limited to increasing the expression of IL-1. The basal andTNF-induced expression of COX-2 was not dependent on the presence of NGF in the

growth media. IL-1 and TNF treatment for 24 h enhanced prostaglandin E2 (PGE2)production 24-fold, which was blocked by pretreatment with the COX-2 inhibitor,NS-398. Exposing cultures to PGE2, IL-1, or TNF for 24 h did not alter PGE2receptor (EP) mRNA levels. These results indicate that TNF and IL-1 induce the

functional expression of COX-2 but not EP receptors in DRG cells in culture andsuggest that cytokine-induced sensitization of sensory neurons is secondary to

prostaglandin production and not alterations in EP receptors.

Link to article at on-line Pain journal at Elsevier.com




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Late in 2007 DeLeo, Sorkin & Watkins in their IASP publicationImmune and glial

regulation of pain devoted 5 chapters (of 23) to the DRG. Chapter 9 described DRGsignaling and erythropoietin as a protective agent against neuropathic pain development(Campana, WM), chapter 10 cited the recognition that DRG satellite cells and

trafficking leukocytes into the DRG may directly affect primary afferent signalingwhich enhances the complexity of glial - immune reactions within the CNS

(McLachlan E). Chapter 21 described the ischaemic compromise due to the metabolicdemands of immune - inflammatory processes in the DRG, as well as describing bothpro-inflammatory (IL-1, IL-6, TNF-alpha) and anti-inflammatory (IL-10) cytokines

found in the Nucleus Pulposus of the disk.

McLachlan EM, Hu P (2007). Inflammation of DRG: Satellite cell activation and

immune cell recruitment after nerve injury. In : Immune and Glial Regulation of PainEd DeLeo JA, Sorkin LS, Watkins LR. IASP Press, Seattle. Ch 10

Neuropathic pain generally developes following lesions of the blood-nerve barrier.

Neurogenic inflammation as a result of mechanical irritation leading to chemical irritants andoedema can precipitate the conditions required for the development of neuropathic pain.

Retrograde axonal signalling from nociceptors that surround the DRG itself can propagateinflammatory reactions around the somata of motor, sympathetic and sensory neuronestriggering the release of chemokines from the glia of satellite cells within the DRG and

astrocytes in the ventral horn. In contrast to the CNS, the blood-nerve barrier around the DRG is very permeable thus

allowing the the neurones to be exposed to circulating proteins (and potentially the extruded

disk material such as the nucleus pulposus (NP) - my thoughts). Transection or ligation of the L5 spinal nerve is followed by degeneration of axons in the

distal branches of the sciatic nerve. Interestingly, the L4 DRG shows mild but distinctinflammatory responses with invasion of macrophages and lymphocytes. This findingindicates that DRG inflammation can be triggered by signals independent of axotomy of it's

sensory neurones. The chronic constriction injury model using loose ligatures around the sciatic nerve there is

recruitment of alpha-beat T-lymphocytes into the DRG and the spinal cord. Amost all areCD8+ T cells. Unless T cells and macrophages in the subarachnoid angle are intravascular,penetration of the capsule is likely to require the upregulation of chondroitin sulphate

proteoglycan degrading enzymes such as metalloproteinases, as has been shown insympathetic ganglia (Leone et al 2005).

The most likely effect of inflammation within the DRG is to reduce discharge threshold ofinjured and non-injured neurones that project centrally in pain pathways.Another factor thatmay raise neuronal excitability and initiate discharge is the relative ischaemia resulting from

the higher metabolic demands of inflammation.

Karppinen J (2007). New perspectives on Sciatica. In : Immune and Glial Regulation

of Pain Ed DeLeo JA, Sorkin LS, Watkins LR. IASP Press, Seattle. Ch 21

A sharp 40-98% decrease in intraradicular blood flow in the L5 and L4 was elicited by anintraoperative straight leg raising test at the angle which produced symptoms of sciatica.

Removal of adhesions normalised blood flow highlighting the importance of mechanicalcompression in the induction of ischaemia.

However, inflammation may induce ischaemia through increased endoneurial pressure fromcapillary leakage similar to a 'compartment syndrome' of the DRG.




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In contrast to nerve roots, the DRG are very sensitive to mechanical compression.

Both mechanical and chemical irritation produce more severe histological damage to thenerve roots than either factor alone.

Hypoxia-inducible factor (HIF), a transcription factor that responds to low oxygen levels,

probably triggers mitogen-activated protein kinase (MAPK) expression and erythropoietinsynthesis.

Tumor necrosis factor alpha is crucial in MAPK activation Exposure of the DRG to IL-1beta, TNF-alpha, and IL-6 increased mechanosensitivity of

DRG and it's receptive fields

Antereograde activation of spinal cord glial cells (astrocytes and microglia) by cytokines canresult in extra-territorial pain and mirror image pain

Herniated disk material contains pro-inflammatory as well as anti-inflammatory (IL-10)cytokines.

See the following link for a greater explanation of the neuro-immune-inflammatory

cascade as it relates to exercise, muscle protein, apoptosis and cognitive behaviouraltherapy.

Immune System and Musculoskeletal Dysfunction

References

Adams, M.A., Dolan, P.& Hutton, W.C. (1986). The stages of disc degeneration asrevealed by discogram. Journal of Bone and Joint Surgery 68B, 36.

Ahmed, M., Bjurholm, A., Kreicbergs, A.& Schultzberg, M. (1993). Sensory andautonomic innervation of the facet joint in the rat lumbar spine. Spine 18(14), 2121 to2126.

Alkon, D.L.& Rasmussen, H.A. (1988). A spatial-temporal model of cell activation.Science 239, 998 to 1005.

Attal, N., Filliatreau, G., Perrot, S., Jazat, F., Di Giamberardino, L.& Guilbaud, G.

(1994). Behavioural pain-related disorders and contribution of the saphenous nerve incrush and chronic constriction injury of the rat sciatic nerve. Pain 59, 301 to 312.

Badalemente, M.A., Dee, R., Ghillani, R., Chien, P-F. & Daniels, K. (1987).Mechanical stimulation of dorsal root ganglia induces increased production ofsubstance P : A mechanism for pain following nerve root compromise? Spine 12, 552

to 555.

Barasi, S.& Lynn, B. (1986). Effects of sympathetic

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